6 6 - difluoro-13beta-ethyl-17alpha-substituted-17beta-hydroxy - 4 - gonen - 3-ones and their lower esters

ABSTRACT

THESE COMPOUNDS ARE HIGHLY ACTIVE PROGESTATIONAL AGENTS.   R1 IS ETHYL, PROPYL, OR ISOPROPYL: R2 IS HYDROGEN, THE ACETYL GROUP, OR THE PROPIONYL GROUP; R3 IS -CH$CH, -C$CCF3, -CH=CH2, -C$CCH3, -CH2CH3, -CH=CHCH3, OR -CH2CH2CH3.   IN WHICH   3-(O=),6,6-DI(F-),13-R1,17-(R2-O-),17-R3-GON-4-ENE   DESCRIBED ARE STEROID COMPOUNDS OF THE FORMULA

United States Patent 6,6 DIFLUORO-13p-ETHYL-17a-SUBSTITUTED-17fl- HYDROXY 4 GONEN 3-0NES AND THEIR LOWER ESTERS George A. Boswell,.Jr., Wilmington, Del., assignor to ED. du Pont de Nemours and Company, W1lm' ington,

No Drawing. Continuation-impart of application Ser. No. 720,493, Apr. 11, 1968, now Patent No. 3,511,861. This application Jan. 22, 1970, Ser. No. 5,139

Int. Cl. C07c 169/20 U.S. Cl. 260-397.4 8 Claims ABSTRACT OF THE DISCLOSURE Described are steroid compounds of the formula in which R is ethyl, propyl, or isopropyl; R is hydrogen, the acetyl group, or the propionyl group; R is --CHECH, C. ='CCF3, CH=CH CECCH '-CH2CH3, OI' -CHZCHZCH3. These compounds are highly active progestational agents.

RELATED APPLICATION This application is a continuation-in-partof my copending application Ser. No. 720,493, filed Apr. 11, 1968, now U.S. Pat. No. 3,511,861.

BACKGROUND OF THE INVENTION This invention relates to new 6,6-difluorosteroids, which are useful as progestational agents.

My copending application Ser. No. 720,493 is directed to certain 6,6-difluorosteroids in which there is in the C-3 position a hydroxyl, an alkoxyl, or an acyl group. These compounds are useful progestational agents.

One of the intermediates disclosed in my said copending application is 6,6-difluoro-13fl-ethyl-17a-ethynyl-17phydroxygon-4-en-3-one, of Formula I,

I OH H 3,647,830 Patented Mar. 7, 1972 SUMMARY OF THE INVENTION It has now been discovered, according to this invention, that certain 17B-hydroxy-, acetoxy-, and propionyloxy-6,6- difluorosteroids have an exceptionally high short-term progestational activity. These compounds can be represented by the general Formula II,

in which R is ethyl, propyl, or isopropyl; R is hydrogen, the acetyl group, or the propionyl group;

and R is one of the following groups: CECH, -CECCH3,

C CCF -CH=CH CH CH H=CHCH and CH CH CH These compounds are especially suitable for subcutaneous administration because of their fast action.

DETAILED DESCRIPTION OF THE INVENTION It will be readily appreciated that 6,6-difluoro-17B-hydroxysteroids of the present invention are at the same time important intermediates in the preparation of the corresponding 17fl-acetyl and -propionyl esters. These hydroxysteroids can be prepared by known methods, starting with available materials.

Thus, the diketone III (which can be made from a methyl ketone and diethyl oxalate by the method of Smith et al., J. Chem. Soc. 1963, 5072, ibid., 1964, 4472, 4487, and 4492) can be condensed under mild conditions with either compound IV or V to form the steroid precursor VI, which is readily cyclized. This reaction sequence is shown below in Scheme 1:

were

cn=cn o o on cs (III) (Iv) Or s (VII) (VI) acetyl group, and TS for the toluenesulfonyl group. Compound IV is made from commercial 6-methoxy-1-tetra1one 'p-TSOH 15 and vinylmagnesium bromide, and it can be converted to c 3 Compound V with thiourea and acetic acid.

The keto group of Compound VII is reduced With tri- (t-butoxy)lithium aluminum hydride to the l7 8-alcohol (VIII), which then is converted in several steps to the 20 corresponding 17B hydroxy 135 alkyl-4-gonen-3-one (XIII), as shown in Scheme 2, below:

Scheme 2 P33 (vII) LiAlHfiO-t-Buh KEEJU' Ac 0 THE py (VIII) OAc R2 OAc H /Pd/CaCO m/mr 2 l #39 J H E 9 CH3O 1 'CH3O L1/NH3 C2350}! HCl/CH on .I 3.

(XII) In the above reaction scheme, the meaning of R is the same as before; t-Bus stands for tertiary 'butyl; Py stands for pyridine; and THE is an abbreviation of tetrahydrofuran. The catalytic hydrogenation of the ring D double bond in Compound IX can be about 95% stereospecific to give the 140t-ISOII11' shown. The lithium/ammonia reduction of the 8(9) double bond in Compound X is stereospecific and gives Compound XI which has the trans-anti-trans B-C-D ring configuration.

Addition of ethanol to the reduction mixture containing Compound XI produces the enol XII which is hydrolyzed by strong acid and rearranges to Company XIII, having the desired trans-anti-trans B-C-D configuration.

In addition to the above Smith et al. references, other total synthesis methods have been reported as follows: Smith et al., Steroids 2, 319 (1963); ibid. 11, 649 (1968); O. H. Kuo, D. Taub, and N. L. Wendler, J. Org. Chem., 33, 3126 (1968); I. N. Nazarov, I. V. Torgov, and G. P. Verkholetova, Dokl. Akad. Nauk SSSR, 112, 1067 (1957 (English translation 112, 167 (1957)).

The 3-ket0-17fi hydroxysteroid XIII is converted to the corresponding enol diacetate (XIV), which is treated with sodium borohydride to give the monoacetate (XV). This compound is reacetylated to (XVI), treated with a mixture of nitrosyl fluoride and nitrosyl fiuoborate to give the Sa-fluoro-6-nitriminosteroid (XVII), and converted by activity Grade III neutral alumina to the corresponding 5a-fluoro-6-ketosteroid (XVIII). Compound XVIII reacts with sulfur tetrafiuoride under mild conditions to give the 5a,6,6-trifluorosteroid, XIX, which is hydrolyzed, oxidized to the 3,17-diketone, XX, and dehydrofluorinated to the A -6,6-difluoro-3,17-dione (XXI). The 3-keta1 of Compound XXI reacts with the lithium salt or Grignard derivative of acetylene, propyne or 3,3,3-trifiuoropropynyl to give the 170t-SllbStitllt6d steroid, which is hydrolyzed to the 3-keto-17;8-hydroxysteroid (XXII) of the present invention. This sequence of reactions is illustrated below by the Scheme 3:

Scheme 3 CH3 l Ac 1; (XIII) AcgO or AcCl Nimitz;

AcO

(XIV) ca form CH 2 L QOAe M20 H No? 2a H p A00 V) (xvr) err c 3 oAe f are "2 "2 H rt 1 o -H 0 sr A 2 3 e g i l 5 (1)HC1/CH3OH A1 0 H o (Si-T in,

i! (1) ethylene glycol H (2) me 5 cs or BrMgC CR5 o (3) 11+ 5 EXAMPLE 1 dl 6,6 difluoro-13fi-ethyl-17B-hydroxy-l7a-ethynyl-4- gonen-3-one. (Formula II; R =ethyl; R =hydrogen; R =ethynyl) A. dl-3,8-17B-diacetoxy-13B-ethy1-4,6-gonadiene H ACZO, ACCl; CsHsN CH3 l oAe CH2 AcO dl-18-methyl-19-nortestosterone (13.8 g.), (prepared by the method of Smith, J. Chem. Soc. 1964, 4472-4495), ml. of acetic anhydride, 60 ml. of acetyl chloride and 6 ml. of pyridine was heated under reflux for two hours; the volatiles were removed, and the residue was crystallized from methanol to give 17.8 g. of dl-3B,17fi-diacetoxy-13fi-ethyl-4,6-gonadiene, M.P. 147-149".

Analysis.-Calcd. for C H O C, 74.16%; H, 8.66%, MW, 372.49. Found: C, 73.99%; H, 8.70%; MW; 372.

B. dl-3p-hydroxy-17fl-acetoxy-13,8-ethyl-5-gonene The product of step A (10 g.) was dissolved in 100 ml. of tetrahydrof-uran, cooled to 0 and treated with 4.17 g. of cold sodium borohydride in 150 ml. of ethanol; and the mixture was stirred for 16 hours. The mixture was poured into ice water (500 ml.) and the solid (8.4 g.) removed by filtration. Crystallization from aqueous methanol gave the 17fi-acetate, M.P. 138460".

7 Analysis.Calcd. for C H O C, 75.86%; H, 9.70%; MW 332.47. Found: C, 76.05%; H, 9.76%; MW 332.

OAC

| ocoon CH A1203-H O K H I Y C11 0 0 0 V, I

NOF

NOBF4 Product of Step 0 CH3 L 000011 F It 0 The product of step C (7.2 g.) in 80 ml. of methylene chloride was added slowly to a cooled (0") solution of 4.67 g. of nitrosyl tetrafluoroborate in 120 ml. of glyme while a total of 6.37 g. of nitrosyl fluoride was introduced in a slow stream. The mixture was allowed to stand overnight, then it was poured into 500 ml. of brine, which was extracted twice with 100 ml. of methylene chloride. The organic solution was dried over sodium sulfate and the solvent evaporated to give 10.47 g. of dl-3,B,l7,B-diacetoxy-Sot-fluoro-6-nitrimino-13,8-ethylgonane. The latter was dissolved in 30 m1. of benzene and passed through 100 g. of neutral alumina of activity grade III (containing 6% water) using 500 ml. of benzene as eluant. The steroid was rechromatographed using hexane, 3:1 by volume hexanezbenzene, and benzene to give 6.94 g. of the dl 3,8,17/3-diacetoXy-5ot-fluoro-l3B-ethylgonan-6-one, which was recrystallized from acetone-hexane, M.P. 150- 154.

Analysis.Calcd. for C H O F (percent): C, 67.62; H, 8.14. Found (percent): C, 67.82; H, 8.07.

E. dl-BB,17B-diacetoxy-5a,6,6-trifluor0-13,8-ethylgonane 000011 CH2 HI /\I/ cmooo- The product of step D, above, (3.2 g.) in 40 ml. of methylene chloride and one ml. of Water was agitated with g. of sulfur tetrafiuoride at 25 for 10 hours. To the mixture was added 225 ml. of methylene chloride; the methylene chloride solution was then washed with Water, 5% NaHCO and brine and dried over MgSO The solvent was evaporated and the product chromatographed on a Florisil column with hexane and 5% by volume acetonezhexane. The center cuts were combined and recrystallized from acetone (10 ml.) and hexane (25 ml.) to give the trifiuorosteroid (2.61 g.), M.P. 169.5- 17l.5.

Analysis.-Calcd. for C H F O (percent): C, 64.17; H, 7.73. Found (percent): C, 64.37; H, 8.00.

H W V;

A solution of 2.45 g. of the preceding trifluorodiacetate from step E in 25 ml. of methanol and 3 ml. of conc. HCl was heated to reflux for one hour. Water was added, and the mixture was cooled and filtered. Crystallization from aqueous acetone gave the diol in 98% yield, M.P. dec.

Analysis.Calcd. for C H R O (percent): C, 65.89; H, 8.49. Found (percent): C, 65.55; H, 8.66.

G. dl-5a,6,6-trifiuoro-l3[i-ethylgona-3,17-di0ne The diol from step F above (2.52 g.) was dissolved in 50 ml. of acetone and stirred for 30 minutes with 6 ml. of 8 N CrO The mixture was diluted with hot Water to give a precipitate of the dione in about 90% yield. Recrystallization from acetone-hexane gave colorless crystals, M.P. 189-190.

Analysis.Calcd. for C H F O (percent): C, 66.65; H, 7.36. Found (percent): C, 67.07; H, 7.61.

The dione obtained according to step G, above, (total of 3.8 g.) was dissolved in benzene and absorbed on a column of g. of neutral alumina of grade III activity. After standing for 30 minutes, it was eluted with one liter of benzene. The benzene was evaporated and the residue crystallized from 90 ml. of acetone/hexane to give 2.87 g. of 6,6-difluoro-13fi-ethy1-4-gona-3,17-dione, M.P. 171-172.

9 Analysis.Calcd. for C H F O (percent): C, 70.78; H, 7.50. Found (percent): C, 72.50; H, 8.18.

I. dl-6,6-difluoro-13fi-ethyl-4-gonen-3,17-dione 3 ethylene ketal The above dione (2.5 g.) was heated under refiux (with a water separator) with 7.5 ml. of ethylene glycol, 2.5 g. of oxalic acid dihydrate and 100 ml. of benzene. After 6.5 hours, the mixture was extracted with 50 ml. of NaHCO solution, 50 ml. of water and dried over Na SO The ketal had M.P. 186-193". The structure was confirmed by infrared and the reaction monitored by TLC (using cyclohexane/ethyl acetate).

Analysis.--Calcd. for C H F O (percent): C, 68.83; H, 7.70. Found (percent): C, 68.86; H, 7.93.

J. 6,6-difluoro-13B-ethyl 17,8 hydroxy 17cc ethynyl-4- gonen-3-one-3-ethylene ketal K. dl.-6,6 difluoro 153,3 ethyl 17 3-hydroxy-17aethynyl-gonen-3-one The crude ketal of step I, above, was stirred with 25 ml. of 90% acetic acid for three hours and poured into 50 ml. of water. The mixture was extracted with three 20 ml. portions of methylene chloride. The extracts were dried, and the solvent was removed by evaporation. The product was purified by preparative TLC on silica gel by cyclohexane/ethyl acetate (1/3) and recovered by acetone (500 ml.). Recrystallization from cyclohexane/ ethyl acetate gave the gonenone, M.P. 163-164".

Analysis.-Calcd. for C H F O (percent): C, 72.39; H, 7.52. Found (percent): C, 72.14; H, 7.43.

EXAMPLE 2 A mixture of 0.01 'mole of the l7fl-hydroxysteroid product of Example 1 with 20 ml. of pyridine and 20 ml. of acetic anhydride is heated under nitrogen at C. with good stirring for a period of six hours. The starting steroid dissolves during this time in the acetylating mixture. The solution is poured into an ice-water mixture, and the product is filtered and washed with ice-cold-water. The crude material is purified by chromatography on Florisil, followed by recrystallization from a mixture of acetone and hexane.

The corresponding propionyl ester, 6,6-difluoro-13B- ethyl-17h propionoxy l7a-ethylnyl-4-gonen-3-one, can be made by the same technique, except that propionic anhydride is used instead of acetic anhydride.

The acylation of the l7 3-hydroxy group can also be accomplished by stirring the 17,9 hydroxysteroid with the acid anhydride in the presence of p-toluenesulfonic acid, as described by Mills, Ringold, and Djerassi, J. Am. Chem. Soc. 80, 6118 (1958).

EXAMPLE 3 dl-6,-6-difiuoro 13p ethyl 17B hydroxy-17a-vinyl-4- gonen-3-one (Formula II; R ethyl; R =hydr0gen R =CH=CH The l7p3-hydroysteroid (0.01 mole) of Example 1 is dissolved in ethyl acetate ml.) and hydrogenated in a Parr shaker at 25 in the presence of a 5% palladiumcalcium carbonate catalyst (0.5 g.) containing quinoline and lead, 0.01 mole of hydrogen being absorbed. The catalyst can be prepared according to the procedure of Lindlar, Helv. Chem. Acta 35, 446 (1952); or a variation thereof, such as Bowers, Ringold, and Denot, J. Am. Chem. Soc. 80, 6115 (1958), which employs palladiumcalcium carbonate, and pyridine. These catalysts reduce the triple bond to the double bond only with the absorption of one mole of hydrogen per mole of streoid. The vinyl compound is recovered from the ethyl acetate solution, which first is filtered to remove the catalyst, then evaporated, and the residue is purified by chromatography on Grade III alumina. The crystalline product finally is recrystallized from a mixture of acetone and hexane.

More energetic hydrogenation of the 17 a-ethynyl-steroid produces the 17a-ethyl compound. Such a reduction can be conveniently carried out in ethanol solution in the presence of palladium on charcoal. The hydrogenation of 0.01 mole of steroid in ethyl acetate (150 ml.) in a Parr shaker at 25 in the presence of 5% palladium on charcoal (0.5 g.) is stopped after 0.02 mole of hydrogen has been absorbed. The same isolation procedure can be used. This general hydrogenation technique is reported by Hershberg, Oliveto, Gerold, and Johnson, J. Am. Chem. Soc. 73, 5073 (1951).

EXAMPLE 4 dl-6,6-difiuoro 13B ethyl 17B hydroxy-17a-(3,3,3-trifluoroprop'ynyl)-4-gonen-3-one (Formula II; R =ethyl; R ='hydrogen; R3=CECCF3) A solution of dl-6g6-difiuoro-13 8-ethyl-4-gonene-3,17- dione-3-ethylene ketal (0.01 mole), the product of the step (I) of Example 1, in tetrahydrofuran (100 ml.) is added to a solution of a Grignard reagent prepared by saturating an ether solution of ethylmagnesium bromide (0.025 mole) with gaseous 3,3,3-trifiuor0propyny1 and filtering in the absence of air and moisture. The combined solution is stirred for six hours at 25 C.; the excess Grignard reagent is decomposed with water, and the product is recovered by extraction with dichloromethane. Pure 6,6-difluoro 13B ethyl-17B-hydroxy-17a-(3,3,3-ti-fluor0- 1 1 propynyl)-4-gonen-3-one is obtained by chromatography on Activity Grade III neutral alumina.

Alternatively, this compound can be made from the 17aethynyl alcohol of Example 1 by the following reaction sequence:

R I l ---c-ccr When propyne is used in place of acetylene in the step (I) of Example 1, dl-6,6-difiuro-1313-ethyl-17B-hydroxy 17a-(l-propynyl)-4-gonen-3-one is produced. Reduction as described in Example 3 yields dl-6,6-diflu0ro-l3fl-ethyl- 17/8 hydroxy-1-7a-(1-propenyl)-4-gonen-3-one and dl-6,6- difluoro-13fi-ethyl 17B hydroxy 17cc propyl-4-gonen- 3-one.

By using the above-described techniques, and starting with dl-18-ethylor dl-l-8,l8-dimethyl-19-n0rtestosterone (prepared by the method of Smith, J. Am. Chem. Soc., 1964, 4472-4495), it is possible to prepare the corresponding 13B-propy1- and 13fi-isopropylsteroids, i.e. compounds of Formula II in which R is propyl or isopropyl. Representative 135-propyland 13,8-isopropylsteroids of this invention include:

6,6-difluoro13B-propyl 17,8 hydroxy-17u-ethynyl-4- gonen-3-one,

6,6 difluoro-lBfi-isopropyl-l7,8-hydroxy-17u-ethynyl-4- gonen-3-one,

6,6-difiuoro 13/3 propyl 17B acetoxy-17a-ethynyl-4- gonen-3-one,

6,6-difluoro-13B-isopopyl 17,8 acetoxy-l7a-ethynyl-4- gonen-3-one,

6,6 difluoro-1313-propyl-17fi-propionyloxy-17a-ethyny1- 4-gonen-3-o11e,

6,6-difluoro 135 isopropyl 1713 propionyloxy 17aethyny1-4-gonen-3-one,

6,6-difiuoro-13fl-propyl 175 hydroxy-17u-propyny1-4- gonen-3-one,

6, 6 difluoro 135 propyl-17/3-hydroxy-17a-trifluor0- propyny1-4-gonen-3-one,

6,6-difluoro 13,8 popyl 17,6 acetoxy-l7u-propynyl- 4-gonen-3-one,

6,6-difiuoro 13B isopropyl 17B propionyloxy-17atrifluoropropynyl-4-gonen-3-one,

6,6-difluoro 13f prop'yl 17B acetoxy-17a-viny1-4- gonen-3-one, and

6,6-difluoro-13B-propyl 17,8 propionyloxy-l7a-ethyl- 4-gonen-3-one.

The streoid compounds of this invention are useful as progestational agents, which show a high activity in shortterm bioassays. The following test procedure is employed:

Immatue female rabbits weighing 800-1000 grams are estrogen-primed by means of daily subcutaneous doses of ,ag. of estradiol benzoate for six consecutive days. Beginning on the seventh day for five consecutive days, the new materials of this invention are administered once daily in 0.5% tragacanth by subcutaneous injection or by gavage. The rabbits are autopsied on the twelfth day. Sections of the uterine tissue are examined microscopically and the uterine weight, ovarian weight and degree of progestationial reaction in the endometrium are determined and compared to norethindrone with a total oral dose of 0.02 mg.

The compound of Example 1, i.e., dl-6,6-difluoro'l3flethyl-17fl-hydroxy-l7a-ethynyl-4gonen-3-one, was found in duplicate tests to be 6 to 8 times as active as norethindrone.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A steroid compound having the general formula in which R is a member of the class: ethyl, propyl, and isopropyl;

R is hydrogen, the acetyl group, or the propionyl group;

and

R is selected from the class: CECH, CEC--CH3,

CEC-CF CH=CH CH 'CH 6. 6,6-difiuoro-13fl-ethyl-17fi-hydroxy-17a-(1-propynyl)- 4-gonen-3-one, the compound of claim 1 in which R is ethyl; R is hydrogen; and R is -CEC-CH3.

7. 6,6-difiuoro-13,3-ethy1-17B-hydroxy-17a-( 1-propenyl)- 4-gonen-3-one, the compound of claim 1 in which R is ethyl; R is hydrogen; and R is -CHECHCH3.

8. 6,6-difluoro-13/3-ethyl-17,8-hydroxy-l7aa-propyl 4- gonen-3-one, the compound of claim 1 in which R is ethyl; R is hydrogen; and R is -CH CH CH References Cited UNITED STATES PATENTS 3,202,686 8/1965 Hughes et a1 260397.45 3,467,652 9/1969 Hughes et a1 260239.55 3,471,531 10/1969 Hughes et al. 260-397.5 3,219,673 11/1965 Boswell 260-3973 HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 

